The modern world has experienced enormous growth in obesity, a disease associated with increased incidence of and mortality from diabetes, cardiovascular disease and cancer. Even moderate weight loss in the range of 5-10% has been shown to prevent the long-term consequences of obesity. Unfortunately, the current treatment options for obesity remain limited in both their application and effect. Our preliminary data indicate that sarcolemmal ATP-sensitive K+ (KATP) channels limit muscle energy expenditure under physiological workload, while KATP channel deficit provokes an extra energy cost of muscle performance. Inefficient fuel metabolism in KATP channel-deficient muscles reduces body fat deposits promoting a lean phenotype. The current proposal builds on this finding to determine the mechanisms by which KATP channel function affects skeletal muscle performance, and adipose tissue mobilization. We hypothesize that membrane potential modulation, due to KATP channel opening in response to a physiological workload, limits calcium and sodium inward currents and thus energy consumption related to ion homeostasis and contraction continuation. Under conditions of surplus calorie intake this promotes weight gain. Conversely, disruption of KATP channel function would result in exaggerated cellular calcium turnover, causing increased energy consumption and activation of calcium/calmodulin dependent protein kinase (Ca2+/CaMKII). We propose, that induction of CaMKII triggers both Akt-dependent production and Ca2+- dependent secretion of a signaling peptide - musclin. This peptide is known for its ability to modulate clearance of atrial natriuretic peptide (ANP) - a potet activator of lipolysis. In this way, musclin signaling could translate increased activity related energy consumption into adipose tissue mobilization. The goal of this project is to directly study the molecular mechanism of KATP channel control of activity- related energy consumption and the mechanism of consequent adipose tissue mobilization and body weight reduction. The proposed investigation will be performed across multiple models - biochemical and electrophysiological studies on cellular and isolated organ levels will be used to verify molecular mechanisms for findings obtained on the whole body level. Understanding these mechanisms will provide novel avenues for targeted management and prevention of obesity and related diseases. PUBLIC HEALTH RELEVANCE: Obesity is occurring at epidemic rates and has exceeded 30% of the U.S. population. Yet despite the medical, social and economic impact of obesity, only a few therapeutic options with limited success rates are currently available. This application addresses the novel hypotheses that metabolism-sensing KATP channels are important regulators of bodily energy balance and weight management, due to the effect of their function on muscle energy efficiency and mobilization of fat, and are potential targets for prevention and treatment of obesity.